Pharmaceutical products for administration to subjects such as humans must contain high purity drug substance preparations and pharmaceutical compositions, and be formulated into dosage forms that contain consistent amounts of an active pharmaceutical ingredient (API).
All drug substance preparations, regardless of the API, contain varying amounts of impurities. These impurities can generally be grouped into categories based on their chemical identity and include “product-related impurities”, i.e., impurities that are structurally similar to the API (e.g., enantiomers) and “process-related impurities”, i.e. impurities introduced by or resulting from the processes used to make the API.
The identification, quantification, and qualification of impurities in pharmaceutical products, especially drug substances and pharmaceutical compositions made therefrom, is a critical aspect of ensuring the safety, efficacy and consistency of chemotherapeutic treatments. However, the characterization of impurities can be particularly difficult to achieve when drug substance preparations are obtained through the use of biological processes, such as fermentation, which are less predictable and controllable than wholly synthetic processes. Biological processes often utilize live prokaryotic or eukaryotic cells to produce a drug substance of interest, and large and intricate sets of impurities can be associated with the often structurally complex substances that are produced. In practice, it is very difficult to fully characterize all potential impurities and understand what impact they might have on safety and efficacy when a drug substance preparation is incorporated into pharmaceutical products. Therefore, the safest path is to minimize impurities in drug substances of interest.
The problematic nature of impurities is particularly acute for dalbaheptides, a class of complex glycopeptide antibiotics related to vancomycin that are important antibacterial agents for patients and healthcare providers facing challenges with the declining number of effective treatments available for bacterial infections. For example, vancomycin was approved for commercialization in the late 1950's, but it was relatively unused until the 1980's, largely in part because of perceived toxicity, and in particular nephrotoxicity and ototoxicity. It is now understood that the reported side effects were due to higher levels of impurities in early lots of the drug, which disappeared with improvements to purity (Moellering, R. C. Jr., Clin. Infect. Dis. 2006, 42, S3; Levine, D. P., Clin. Infect. Dis. 2006, 42, S5).
The importance of highly controlled purification of compounds in this class is further demonstrated by the fact that small changes in chemical structure can lead to drug substance preparations with widely different safety and/or efficacy profiles. For example, rapid infusion of vancomycin into subjects has been associated with the “red man” syndrome, a histamine-like response characterized by a combination of erythema, pruritis, hypotension, and angioedema, which is not seen during infusion of the closely-related drug teicoplanin (Levine, D. P., Clin. Infect. Dis. 2006, 42, S5; Sahai. J. et al., Antimicrob. Agents Chemother. 1990, 34, 765). Similarly, telavancin, another drug with a highly similar chemical structure, was shown to be teratogenic in animal models while both vancomycin and teicoplanin were non-teratogenic in the same models (Damodaran, S. E., Madhan, S. J., Pharmacol. Pharmacother. 2011, 2, 135).
Small changes in chemical structure can also lead to unforeseen impacts on antibacterial activity in terms of either spectrum or potency. For example, compound A40926 is closely related to teicoplanin but it is much less active against coagulase-negative staphylococci, whereas dalbavancin is more potent than teicoplanin by an order of magnitude against these same microorganisms (Malabarba, A., Goldstein, B. P. J., Antimicrob. Chemother. 2005, 55 Suppl. S2, ii15).
It is thus evident that the development of high purity drug substance preparations and pharmaceutical compositions comprising dalbaheptides for use in pharmaceutical products, with both a reduced number of impurities and a decreased amount of those impurities that cannot be completely removed, is an important goal. The present invention is directed to this and other important goals.